Oxidative stress represents an imbalance between cellular reactive oxygen species (ROS) production and cellular responses to ROS such as degrading ROS species and producing endogenous anti-oxidant molecules. When left unchecked, increased ROS levels in a cell can result in damage to components such as lipids, proteins, polysaccharides, and DNA. Prolonged oxidative stress is also linked to chronic diseases that affect nearly every major organ system. For example, prolonged activation of oxidative stress is implicated in the onset or progression of disease states such as neurodegenerative diseases, lung diseases, cardiovascular diseases, renal diseases, diabetes, inflammatory pain, and cancer. Accordingly, strategies to mitigate oxidative stress are desirable for a number of therapeutic settings.
Heme oxygenase (HMOX1) is an enzyme that degrades heme to produce the cytoprotective molecules iron, biliverdin, and carbon monoxide, which have antiapoptotic, antiinflammatory, and antioxidant effects. HMOX1 expression is ubiquitously induced in mammalian tissues in response to diverse stressors, such as ultraviolet radiation, endotoxins, heavy metals, and oxidative stress. HMOX1 expression is also induced in numerous disease and injury states, such as atherosclerosis, ischemia, hypertension, chronic obstructive lung disease, hyperoxia-induced lung injury, acute renal failure, and cancer (see, e.g., Otterbein and Choi, Am. J. Physiol. Lung Cell. Mol. Physiol. 279:L1029-L1037 (2000)). It has been shown that the regulation of HMOX1 protein levels leads to changes in pathophysiology in disease models. For example, mice that are deficient for HMOX1 exhibit increased severity of disease symptoms such as pancreatitis in models of diabetes, increased intimal thickening in models of vascular injury, and increased plaque formation in apolipoprotein E (APOE) deficient mice; adenoviral gene transfer of HMOX1 ameliorates pathology in animal models of hyperoxia induced lung injury, islet transplantation survival, ischemia reperfusion in rats and mice, and in atherosclerotic lesion formation in APOE deficient mice; and pharmacological regulation of HMOX1 leads to amelioration of pathology in animal models of cardiovascular disease. The combination of epidemiological association studies, genetic models, and animal pharmacology findings support a protective role for HMOX1 and indicate that therapeutic elevation of HMOX1 in disease settings can be adaptive and protective.